Mesenchymal stem cells (MSC) represent a promising cell source for regenerative medicine applications. Transplanted MSC enhance bone, cartilage, and intervertebral disc repair in pre-clinical models and initial clinical trials. Howevr, the engraftment of transplanted MSC is extremely low, and the beneficial effects are generally attributed to trophic/paracrine actions. The low engraftment and survival of transplanted MSC significantly limit these cell-based therapies in the repair of challenging, non-healing defects. A major hurdle to MSC survival and engraftment is the lack of appropriate bioactive delivery vehicles. The objective of this project is to engineer biofunctional hydrogels to direct human MSC (hMSC) survival, engraftment, and function. Our central hypothesis is that hydrogels presenting integrin-specific adhesive ligands will promote hMSC engraftment, osteogenesis, and bone repair. This work will establish bioactive cell delivery vehicles that enhance MSC survival, engraftment and function compared to existing synthetic matrices. Aim 1: Engineer hydrogels presenting integrin-specific adhesive ligands to direct hMSC fate commitment and differentiation. Aim 2: Evaluate the ability of integrin-specific hydrogels to promote hMSC survival, engraftment, and bone repair. Aim 3: Analyze the effects of VEGF co-delivery from hydrogels on hMSC engraftment and bone repair. The proposed research is innovative because it focuses on exploiting integrin binding specificity to control hMSC survival, engraftment and function for bone repair and integrates new in vivo imaging approaches. This work is expected to yield the following outcomes. First, we will determine the extent to which integrin-specific ligands regulate hMSC signaling, commitment and differentiation into osteogenic, adipogenic and chondrogenic lineages. We will also establish novel bioactive cell delivery vehicles that enhance MSC survival, engraftment and bone formation for improved bone repair. Finally, because of the transformative potential of MSC, this research will have broad significance and impact to many regenerative medicine applications. PUBLIC HEALTH RELEVANCE: Mesenchymal stem cells represent a promising cell source for regenerative medicine applications. We will engineer biofunctional hydrogels to direct human mesenchymal stem cell survival, engraftment, and function. We will establish novel bioactive cell delivery vehicles that enhance stem cell survival, engraftment and bone formation for improved bone repair.